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  Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core

Pak, A. J., Yu, A., Ke, Z., Briggs, J. A. G., & Voth, G. A. (2022). Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core. Nature Communications, 13: 1002. doi:10.1101/2021.05.24.445443.

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s41467-022-28654-5.pdf (Publisher version), 3MB
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bioRxiv, 2021-06-16

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 Creators:
Pak, Alexander J., Author
Yu, Alvin, Author
Ke, Zunlong, Author
Briggs, John A. G.1, Author              
Voth, Gregory A., Author
Affiliations:
1MRC Laboratory of Molecular Biology, External Organizations, ou_3346673              

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 Abstract: The molecular events that permit the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to bind, fuse, and enter cells are important to understand for both fundamental and therapeutic reasons. Spike proteins consist of S1 and S2 domains, which recognize angiotensin-converting enzyme 2 (ACE2) receptors and contain the viral fusion machinery, respectively. Ostensibly, the binding of spike trimers to ACE2 receptors promotes the preparation of the fusion machinery by dissociation of the S1 domains. We report the development of bottom-up coarse-grained (CG) models validated with cryo-electron tomography (cryo-ET) data, and the use of CG molecular dynamics simulations to investigate the dynamical mechanisms involved in viral binding and exposure of the S2 trimeric core. We show that spike trimers cooperatively bind to multiple ACE2 dimers at virion-cell interfaces. The multivalent interaction cyclically and processively induces S1 dissociation, thereby exposing the S2 core containing the fusion machinery. Our simulations thus reveal an important concerted interaction between spike trimers and ACE2 dimers that primes the virus for membrane fusion and entry.

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Language(s): eng - English
 Dates: 2022
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Type: -
 Identifiers: Other: 34127973
DOI: 10.1101/2021.05.24.445443
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Title: Nature Communications
  Abbreviation : Nat. Commun.
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 13 Sequence Number: 1002 Start / End Page: - Identifier: ISSN: 2041-1723
CoNE: https://pure.mpg.de/cone/journals/resource/2041-1723